A comprehensive review of cell transplantation and platelet‐rich plasma therapy for the treatment of disc degeneration‐related back and neck pain: A systematic evidence‐based analysis

Abstract Low back pain (LBP) and neck pain predominate as the primary causes of disability. Cell‐ and platelet‐rich plasma (PRP) products are potential therapies with clinical trials and reviews promoting their efficacy. Nonetheless, they frequently disregard the clinical significance of reported improvements. In this systematic review, the effectuated improvements in pain, disability, quality of life (QoL), and radiographic images are comprehensively described and scored on their clinical significance. An electronic database literature search was conducted on July 2023 for in‐human assessment of cell or PRP products to alleviate discogenic pain. Papers were screened on quantitative pain, disability, QoL, radiographic improvements, and safety outcomes. Risk of bias was assessed through MINORS and Cochrane Source of Bias tools. Reported outcomes were obtained, calculated, and assessed to meet minimal clinically important difference (MCID) standards. From 7623 screened papers, a total of 80 articles met the eligibility criteria, presenting 68 specific studies. These presented at least 1974 treated patients. Overall, cell/PRP injections could alleviate pain and disability, resulting in MCID for pain and disability in up to a 2‐year follow‐up, similar to those observed in patients undergoing spinal fusion. Included trials predominantly presented high levels of bias, involved heterogeneous study designs, and only a minimal number of randomized controlled trials. Nonetheless, a clear clinically significant impact was observed for cell‐ and PRP‐treated cohorts with overall good safety profiles. These results highlight a strong therapeutic potential but also underline the need for future cost‐effectiveness assessments to determine the benefits of cell/PRP treatments.

profiles.These results highlight a strong therapeutic potential but also underline the need for future cost-effectiveness assessments to determine the benefits of cell/PRP treatments.

K E Y W O R D S
back pain, cell therapy, clinical significance, clinical trial, discogenic pain, neck pain, platelet-rich plasma, regenerative medicine, spine, systematic review

| BACKGROUND
2][3] It entails the introduction of de novo cells that replace, complement, or provide a new capacity to the endemic population in the body.The transplanted cells can thereby integrate in situ and support tissue production or general homeostasis or, alternatively, may involve a temporal presence targeted at directing, activating, or attracting native cells. 4As such, the application of (stem) cells as a means of therapy poses a potential paradigm shift in medicine.The most established form of cell therapy involves the transplantation of bone marrow aspirates in treated leukemia patients to repopulate their depleted bone marrow.Since then, new techniques and ideas have led to the development of cellular transplantation products for a range of applications, for example, oncogenic CAR-T, receding gum allografts, and cord blood products. 5,6e predominant applications of cell therapy are focused on hematological and tumorous diseases, followed by their usage in the motor system, central nervous system, autoimmune or graft versus host diseases. 7Here, transplants are proposed to effectuate their therapeutic effect either by limiting pathological inflammatory or immunogenic conditions or by supporting/stimulating the regeneration of diseased tissues.These aspects provide the prospect for the repair of tissues with limited inherit regenerative capacity, for example, cartilage and nervous system tissues, that were previously considered unmendable and thus have garnered significant attention.
Low back pain (LBP) and neck pain form the primary causes of disability worldwide and present an exceptionally high economic burden on societies. 8The 2021 global burden of disease study has once again highlighted the severe impact of LBP, 8 particularly among the workforce population. 9Although LBP and neck pain are recognized as multifactorial diseases, [10][11][12][13] a plurality of cases are found to be associated with the degeneration of the intervertebral disc (IVD) 12 (Figure 1a,b).Here, the fibrocartilage IVD structure progressively loses F I G U R E 1 Illustration presenting the general structure of the intervertebral disc (IVD) and the impact of disc degeneration and cell therapyderived regeneration.(A) A healthy IVD as an entire unit, including the nucleus pulposus (NP), annulus fibrosis (AF), and vertebra with facet-joints.(B) Progression of disc degeneration illustrated by loss of matrix quality, AF-organization, loss of endplate permeability, and NP cell viability and activity, which in turn may promote nerve ingrowth.(C) Transplantation of de novo cells or PRP products into the disc, vertebrae, or epidural space, may support (D) regeneration of the IVD as hallmarked by improvement in cell quantity and quality, tissue organization, nerve ingrowth and sensitization, biomechanical features, and disc features such as height and hydration.AF, anulus fibrosus; IVD, intervertebral disc; NP, nucleus pulposus; PRP, platelet-rich plasma.its specialized organization involving a central hydrophilic nucleus pulposus (NP) and a meticulously organized lamellar annulus fibrosus (AF). 14Due to severely restricted vascularization, limited to the regions bordering the vertebrae (i.e., the endplates) and the peripheries of the outer AF, the IVD is burdened with a limited self-repair capability. 15[24][25] Despite increasing efforts, treatment strategies for discogenic LBP remain primarily palliative or are centered on full immobilization or resection of diseased tissues. 26Such methods, for example, arthroplasty and spinal fusion, are costly and invasive surgeries that come with a high risk of adjacent segment disease, involving the promotion of degeneration in neighboring IVDs. 279][30] Despite stated limitations, these surgeries are becoming more frequent and are speculated to continue to increase drastically in the coming years. 31Therefore, new methods of intervention are highly desired, specifically, methods to alleviate discogenic pain to prevent or extend the need for surgery as well as agents that target the underlying pathophysiology of LBP.Thus, regenerative strategies e.g., tissue engineering, 32,33 growth factor injection, 34,35 extracellular vesicles, [36][37][38] biomaterials, 39,40 and gene therapy 41 are highly anticipated techniques.Specifically, cell therapy 42 and plateletrich plasma (PRP) 43 derived products are posed as a golden opportunity owing to its proposed ability to tackle the decline in cell function and cell numbers that are fundamental to the degenerative cascade and discogenic pain (Figure 1c,d).Multiple in vivo studies have emphasized the strong capacity of intradiscal cell injection to limit, halt, or reverse induced disc degeneration features. 44Since then, multiple in human studies have attempted to alleviate discogenic pain and disability and promote regeneration of disc features in naturally occurring disc degeneration.6][47][48][49] Nonetheless, these reviews are highly speculative and fail to fully present the scale and impact of the claimed "improvements."For a comprehensive understanding of their impact, it is crucial to evaluate not only statistically significant improvements but also their clinical significance.Furthermore, improvements are ideally compared to control conditions (e.g., placebo controls or standard of care, e.g., spinal fusion surgery) to fully identify their added value. 50Only a single meta-analysis by Wu et al. 51 on this topic has been published, which underscores the potential of cellular therapeutics.Nevertheless, this review was severely limited by the small number (N = 6) of eligible controlled and randomized clinical trials.Moreover, the reported outcomes were not discussed in a frame of clinical significance.As such, a need exists to comprehensively examine the overall improvements reported by cell or PRP therapy against discogenic pain and determine whether these observations are productive in a clinical setting and competitive with standard methods of care.
With this systematic review, we aim to capture the full course of pain and disability changes for discogenic LBP patients treated with investigational cellular and PRP therapeutics, presenting the complete observation of changes from baseline scores to final follow-up and assessing their clinical significance.Moreover, by comparing the different trends in pain relief against patient cohorts treated with spinal fusion, we aim to identify the impact of regenerative cellular treatment strategies and their value as prospective orthopedic medical agents.Screening was performed based on article title and abstract, followed by final full text assessment (Figure 2).Papers were excluded if the product was employed to induce spinal fusion or treat cancer.

| Data collection and presentation
The literature was analyzed to determine which reports described identical studies, for example, the same trial but different follow-up times (see  Finally, the risk of bias was assessed independently by both reviewers using the methodological index for nonrandomized studies (MINORS) scheme. 59Additionally, for randomized controlled trials, the Cochrane Source of Bias tool was employed. 60Final presentation of collected data was realized using GraphPad Prism v10.0.2 (GraphPad Software LLC) and Adobe Illustrator version 27.8.1 (Adobe Inc.).

| Systematic literature search and screening
Our systematic review yielded a total of 11 183 papers, of which 7623 papers were manually determined as non-duplicates.Subsequent title and full-text screening found 80 papers to match our inclusion criteria (Figure 2; see Data S2 for reference list).Further assessment determined that these 80 papers comprised a total of 68 separate clinical trials/studies.This encompassed a (minimum) total of 1974 cell/PRP-treated patients.The frequency of publications showed an overall increase over time (Figure 3a,b).The largest number of publications originated from North America (42.5%),where Asian and European countries presented 32.5% and 23.8% of reports, respectively (Figure 3c).This trend is slightly nuanced when examining the number of separate trials (Table 1 and Figure 3d).The identified trials were marked as prospective in 56% of reports (Figure 3e).Randomization and blinding were only reported in 28% and 21% of articles, respectively.Moreover, only approximately one-third of trials included a control group, of which only 38% employed a placebo cohort.Of the 68 studies identified, 52 (76.5%) included some efficacy outcomes, and 63 studies (92.6%) recorded outcomes on adverse events (Table 1).The overall risk of bias assessment revealed a general high risk of bias for the included studies (Data S3).
The included studies recruited a wide range of patients; however, notably, specific aspects of disc degeneration and the diagnosis of LBP were often not specified.Notably, with regard to pain indications, only 43% of trials specified LBP as discogenic, with 54% of trials making no such specification (Figure 3f).Here, only 29% of studies employed discography to confirm the pain source of their cohorts, while 6% had listed discography as an exclusion criterion.
Approximately a quarter of studies included radiculopathy as an inclusion criterion, while equal parts stated it as an exclusion criterion, had a mixed selection, or did not specify this aspect of their patient cohort.Regarding disc degeneration, a large majority (90%) of studies required disc degeneration to be confirmed via MRI (Figure 3g).Disc herniation was used as an inclusion criterion for 34% and as an exclusion criterion for 24% of studies.High-intensity zones or Modic changes were most often not specified but were used as exclusion criteria in a minority of studies.
The included studies employed a wide variety of different products and transplantation strategies (Data S4).The most common products were general PRP products, representing 54.4% of the identified studies (Figure 4a).Next was the transplantation of mesenchymal stromal cell (MSC)-based products (14.7%), followed by chondrogenic cells (13.2%).In addition, 10.3% of studies employed a direct bone marrow aspirate (BMA) product.Considering the high rate of studies applying PRP products, unsurprisingly, the rate of autologous transplantation products was high at 85.3% (Figure 4b).The largest number of studies applied their product through intradiscal injection (64.7%), whereas some PRP products were also administered epidurally (13.2%) (Figure 4c).For the intradiscal injection, needle gauge size was often not specified (43.2%; especially for PRP products), and the most commonly reported needle size was 22 G in 27.3% of studies (Figure 4d).A specialized carrier was not commonly employed, that is, injection of a PRP-derived product (55.9%)or a saline solution (4.4%) (Figure 4e).Alternatively, hyaluronic acid (HA)based gels at 5.9% or disc tissue grafts at 4.4% represented the most common carriers.Notably, 19.1% of reports did not specify the transplantation carrier.

| Pain alleviations
Of the identified studies, 49 separate trials reported pain outcomes based on VAS, NRS, or NPS (Table 2 and Data S5).All studies were able to report a trend of enhanced pain reduction, with most studies able to maintain their obtained alleviation for the duration of the follow-up (Data S5a).The exceptions are the studies by Ruan et al., 61 Ruiz-Lopez et al., 62 and the spinal chain injection group for El-Kadiry et al. 63 No clear differences between the cell and PRP-treated cohorts were observed (Data S5c,e).The median average baseline score was 6.5 and ranged from 0.9 to 9.0 (Table 2).These showed a reduction of a median of 3.7 points, ranging from À0.5 to 9.0 at the final followup.The clear exception was the work of Meisel et al., 64,65 in which cells were injected after discectomy, which was already able to promote most pain alleviation prior to cell injection, resulting in a baseline score of 1.9.Similarly, Ruan et al. 61 started with an average 0.9 neck pain score in their 5-patient cohort; the relatively low baseline levels resulted in overall worsening of pain levels at their 72-month followup.Excluding these two studies, the overall pain reduction of the other trials ranged from 1.2 to 9.0, with a median of 3.8 points (Table 2).This equates to an estimated median relative change of 12 months, and a 2.4 score at 24 months can be expected (Figure 5a; based on 876, 604, and 192 patients, respectively).Alternatively, a pain reduction of 3.4 (N = 1095) at 6 months, 3.2 (N = 835) at 12 months, and 3.4 (N = 343) at 24 months was observed (Figure 5b).
Our data suggest an overall higher trend for cell-based treatments (Figure 5c), where cell-treated cohorts resulted in final pain reductions of 3.5, 3.6, and 4.6 at 6 months, 12 months, and 24 months, respectively (Figure 5d).Compared to 3.4, 2.7, and 2.4 for PRP-treated cohorts.In contrast, MCID comparisons suggested that MSC and chondrogenic cell therapies (except for Meisel et al. 64,65 and Ruan et al. 61 ) were all able to report clinically significant improvements, while BMC and PRP products showed varying results (

| Disability recovery
For our review, 32 separate trials were identified (Table 3) that reported on ODI improvements.All studies were able to report some degree of ODI reduction with different degrees of success (Data S6a, b).From a median baseline ODI (excluding Meisel et al. 64,65 ) of 46.1 MCID for 12 out of 18 (67%) and 13 out of 18 (72%) treated studies at 6 and 12 months, respectively, while PRP reported 7 out of 10 (70%) and 4 out of 5 (80%) (Table 3).If MCID success rates are compared for each study at their final follow-up, a rate of 76% (26 out of 34) was reported.

| Quality of life improvements
Studies that applied QoL assessment through SF12 or SF36 were limited; 12 trials were identified (Data S7).SF12/36 outcomes did suggest a trend of enhanced outcomes for physical components of the survey; however, often little change or even aggravation was Here, a notable observation is the trend of general enhanced results for therapies complementing microdiscectomy.

| Radiographic image improvements
The number of studies reporting on quantitative imaging measurements was notably small, with only 14 separate trials identified in our review (Data S8).Additionally, the types of imaging measurements were diverse and included MRI intensity values (N = 6), ADC (N = 1), disc height (N = 5), and Pfirrmann classifications (N = 9).Overall, these studies show the ability to generally limit the rate of degeneration.Specifically, when looking at the Pfirrmann classification, all the cell-treated cohorts presented a sporadic improvement (ignoring studies involving cell injection to complement microdiscectomy), while the PRP trials showed general maintenance of Pfirrmann classification in their follow-up.Reductions in disc height or MRI intensity were only reported in studies involving transplantation supplementing microdiscectomy or in which the entire disc was replaced by an allograft.

| Safety assessment
Of the 63 trials, studies, and case reports mentioning adverse events, 14 studies reported the occurrence of SAE (Data S9).Specifically, 30 separate SAEs or 34 separate patients were identified in a total patient population of at least 1906 patients, equating to an SAE rate of 1.8%.It is noteworthy that the most common SAEs were related to disc (re)herniation and infectious complications.Moreover, the most serious complications were derived from case reports, specifically discussing often ill-defined cell treatments.

| Safety observations
Cell transplantation and PRP injection appeared to be remarkably well received.Limited SAEs are reported at a rate of 1.8%.This review does suggest a lower rate of complications for PRP products (0.5%) compared to cell injection (4.5%).Notably, the reported SAEs commonly involve events associated with disc degeneration, for example, reports of disc (re)herniation.These events could indicate treatment failure rather than a complication of the treatment.An additional repeating SAE is infectious in nature, such as bacteremia, discitis, and osteomyelitis.These SAEs highlight the risks associated with introducing foreign agents into the disc environment and with ex vivo production processes. 66Nonetheless, the rate of reported infectious SAEs remains low, at approximately 11 per 1906 patients (0.6%).These values are lower than those reported for spinal fusion surgery.For example, a meta-analysis on surgical site infections after spine surgery revealed a rate of 3.1%. 67Moreover, our observations are similar to the findings of Jerome et al. 68 on infectious complications following intradiscal PRP therapies, with a rate of 0.5%.This is despite a bias in our work associated with our inclusion of case reports specifically reporting on observed SAEs.Considering all these limitations and review aspects, cellular and PRP therapeutics present an overall favorable safety profile. 50

| Efficacy trends
The average pain and disability scores and respective reduction rates showed an evident trend of enhanced recovery for both PRP-and cell-treated cohorts (Figure 6).Cell therapies might present higher rates of pain recovery and PRP-enhanced outcomes regarding ODI scores (although the number of involved studies is limited).However, critically, these improvement rates are ideally compared to standard care.Here, we compared the trends observed here to those reported in a meta-analysis by Koenders et al., 55 who analyzed pain and ODI reduction rates over 2 years in LBP patients following surgical fusion surgery.Their results are included in Figure 6 and show a decrease in LBP from 6.4 to 2.0 and a decrease in ODI from 44.8 to 17.3 over 2 years of follow-up.Notably, the baseline and final scores appeared very similar to the data obtained from the cell-and PRP-treated cohorts (Figure 6).Fusion surgery was able to engender a slightly faster pain and disability improvement (although the differences appear small; Figure 6a,c), but the long-term outcomes are similar to trends of cell/PRP-based therapies observed in our review.More specifically, fusion surgery did result in higher rates of pain alleviation than PRP injections but was outperformed by PRP injections when examining disability outcomes.Alternatively, cell therapy demonstrated almost identical long-term benefits to spinal surgery in both pain and disability outcomes (Figure 6c,d).Here, it should be considered that for fusion, the painful disc is excised and fused under invasive surgery, resulting in restrictions in the patients' range of motion 69 and risking the promotion of disc degeneration in adjacent discs. 70,71Comparatively, cell or PRP injection involves a much less invasive procedure and is able to preserve the general disc tissue (or even restore it; Data S8), and based on current data, it is suggested to have limited associated complications, making these regenerative strategies a desirable approach.Nonetheless, careful costeffectiveness studies have not yet been reported and will be required to fully appreciate the potential impact of cell and PRP injections.both VAS and NRS pain scores, an MCID threshold of 2.5 points reduction is suggested (Figure 6b).Based on these recommendations, we illustrated a general trend to present MCID starting from 3 months, which was maintained for cell treatment for up to 2 years.Only PRP injections slightly receded below this threshold after 12 months.Similarly, MCID for ODI outcomes have been proposed; for example, Fairbank et al. 72 had suggested an ODI of 20 to be considered successfully alleviated from disability (Figure 6c).The results from the fusion meta-analysis discussed by Koenders et al. 55 could reach this threshold from 3 months onwards, the cell/PRP-treated patients in this review only approached this threshold and reached this MCID threshold at the 24-month followup.PRP was able to reach this threshold at 12 months, but no longer follow-up data were available.Alternatively, the proposed MCID of a 17-point change in ODI 58 was fulfilled by both cell and PRP therapy at 1 month (Figure 6d) post-transplantation.These observations thus highlight the ability of both PRP and cell injection to limit pain and disability outcomes in a clinically significant manner.Notably, however, the impact and significance of these MCID standards should be carefully considered.
No consensus for a universal MCID exists, and it is likely to be stringently impacted by included pathologies and patient selection criteria. 73,74

| Patient stratification
While the overall improvements suggest that cell/PRP injections are beneficial, it is important to consider the heterogeneous population reviewed here (see Data S10), including both lumbar and cervical disc injections and patients with varying conditions (e.g., herniation, radiculopathy, and spondylosis).Various therapeutic approaches are utilized, including the injection of cellular products to directly address pain and degeneration, as well as their supplementation to discectomy or even full disc replacement.As such, care should be taken when considering the averages reported in this review.It is likely that certain patient stratification will enhance the potential for pain relief or disc augmentation. 757][78] Another critical restriction is the inability to link objective radiographic findings to subjective pain and disability. 79,80This likely hinders both optimal patient stratification and outcome assessment during the trials.MRI developments aim to overcome these shortfalls but are likely still far from clinical adaptation. 79

| Product design and transplantation strategy
Our systematic review identified a wide range of investigated cellular and PRP-based products with a preference for PRP products.Here, however, the radiographic data suggest that the PRP products had primarily palliative effects and showed predominant maintenance of the disc state (Data S8).In contrast, the cell-transplanted cohorts did report sporadic disc improvement.Notably, the impact of these observations is severely limited by the small number of studies reporting quantitative MRI findings.As such, further research is needed to confirm these observations.Additionally, cell and PRP injections were most commonly applied intradiscally, despite the additional damage caused by the required disc puncture, which has been shown to promote disc degeneration. 4,81Alternative strategies, such as epidural and intraosseous transplantation, have also been successfully applied in some of the reviewed trials and might provide interesting venues for further research.

| Limitations and strengths
This review examines the use of PRP and cell-based therapies for the alleviation of LBP and neck pain.Although the primary efficacy of PRP is attributed to the signaling factors within its enriched platelets, the final transplantation product is unlikely to be completely devoid of cells. 84Consequently, we considered it necessary and beneficial to include PRP in this analysis.Nevertheless, given the distinct therapeutic mechanisms speculated between PRP and cell therapies, we also aimed to carefully analyze PRP and cell injections separately.Next, this review is the first to provide a meta-analysis of the complete collection of cell-and PRP-based therapies against disc degeneration and back/neck pain.The observations and values reported in our review can be of tremendous value for future clinical trials to determine optimal cohort sizes through power analysis.Moreover, with more lenient inclusion criteria of reports, we allowed for a more holistic overview of outcomes and prevented repeated overemphasis on a small selection of randomized controlled trials.In contrast, our review is limited by the inclusion of a relatively heterogeneous patient population, treatment strategies, and outcome measures.Moreover, although we analyzed the general average outcomes per trial, the current presentation of the data was unable to consider the variability in outcomes for each included study.In addition, the included studies presented an overall high risk of bias, and many failed to clearly report on specific outcome parameters.

| CONCLUSIONS
Cell and PRP transplantation for LBP and neck pain is a promising technique that could provide, for the first time, a targeted therapeutic agent to resolve the underlying cause of discogenic pain.Our review highlights the potential of these products to result in an average reduction of 3.2 points on the pain scale and 27.0 points on ODI at the 1-year follow-up with a generally good safety profile.These outcomes represent clinically important changes that approach similar reduction rates as patients treated with spinal fusion techniques.As such, from contemporary trials, we can conclude that cell and PRP injections are potent tools to alleviate discogenic pain.Nonetheless, further studies are needed to establish their regenerative potential and determine their cost-effectiveness to ensure optimal allocation of health care spending.
and PRISMA guidelines,53 the initial phase of this review involved a comprehensive systematic search of PubMed, Scopus, and Web of Science online databases (date of search: July 7, 2023) employing the syntax presented in Data S1, Supporting Information.Two researchers (ST and JS) independently screened all articles using RAYYAN software.54Only reports in English that (1) involved transplantation of a cellular or PRP (derivative) product as the primary therapeutic, (2) applied to affect (in part) the IVD, (3) involved in-human assessment, and (4) described safety and/or efficacy assessments were included.Safety assessment involved reporting the number or rate of serious adverse events (SAEs) following transplantation.Efficacy reporting required the description or graphical presentation of pain (visual analog score [VAS], numerical rating scale [NRS], numerical pain scale [NPS]), disability (Oswestry Disability Index [ODI]), quality of life (QoL) outcomes (Short form [SF]-12 or SF-36), and/or radiographic outcomes (T2 intensity, apparent diffusion coefficient [ADC], Pfirrmann grade, disc height) with (calculable) average values of absolute outcomes or change from baseline outcomes.

63 . 56 b
8%, with a range of 15.0%-100%, with no clear differences between PRP or cell-treated cohorts (Data S5).More specifically, a median change of 3.4 (range: 1.1-9.0)and 3.8 (range: 0.6-7.0)points could be determined at the 6-and 12-month follow-ups, respectively.Estimating the overall average pain and pain reduction values by weighing each study result by the cohort sample size, the results in the data presented in Figure 5a-d suggest that with an average baseline pain score of 6.6 points, a 2.8 score at 6 months, a 2.7 score at F I G U R E 3 Figure panel presenting trends in cell-and PRP therapy trials and publications.All identified papers sorted per year of publication and (A) continents of origin and (B) type of report.Pie charts presenting the rate of (C) publications and (D) separate trials reported per country and continent.Pie charts representing the proportions of (E) prospective, randomized, blinded (in any form), and controlled and subsequential placebo-controlled trials identified in our systematic review.Pie charts presenting indications regarding patients including with regard to (F) pain (states discogenic pain, applied discography to confirm painful disc, or presence of radiculopathy) and (G) disc degeneration (MRI confirmed, presence of disc herniation, high intensity zones, and Modic changes).HIZ, high intensity zone; MRI, magnetic resonance imaging.F I G U R E 4 Figure panel presenting trends in cell-and PRP products and transplantation strategies.(A) Pie chart of the rate of different cell types employed in the identified studies.Pie charts of (B) mode, (C) injection site, (D) gauge size of intradiscal products, and (E) carrier employed for transplantation.AC, articular cartilage cells; AD-MSC, adipose-derived mesenchymal stromal cells; BMA, bone marrow aspirate; BMC, bone marrow concentrate; BM-MSC, bone marrow mesenchymal stromal cell; Cul media, cell culture media; Gel sponge, gelatin sponge; HA, hyaluronic acid; IVD-C, intervertebral disc cells; LP-PRP, leukocyte poor/free platelet-rich plasma; LR-PRP, leucocyte-rich platelet-rich plasma; MPC, mesenchymal precursor cells; NP, nucleus pulposus; NPC, nucleus pulposus cell; PEG, Poly(ethylene glycol); PL, platelet lysate; PRP, platelet-rich plasma; SVF, stromal vascular fraction; UC-MSC, umbilical cord mesenchymal stromal cells.T A B L E 2 Tabular overview of reported pain improvements.Table of all identified studies and a summarizing statement regarding the reported pain scores and pain improvements at the final follow-up time point.Abbreviations: AC, articular chondrocyte; AD-MSC, adipose-derived mesenchymal stromal cells; BMA, bone marrow aspirate; BMC, bone marrow concentrate; BM-MSC, bone marrow mesenchymal stromal cells; FU, follow-up (in years); IVD-C, intervertebral disc cells; LP-PRP, leucocyte poor platelet-rich plasma; LR-PRP, leucocyte-rich platelet-rich plasma; MCID, minimally clinical important difference; MPC, mesenchymal precursor cells; NPC, nucleus pulposus cell; NRS, numerical rating scale; PL, platelet lysate; PRP, platelet-rich plasma; PSCI, posterior spinal chain injection; SVF, stromal vascular fraction; UC-MSC, umbilical cord mesenchymal stromal cells; VAS, visual analogue scale.a Following recommendations of Ostelo and de Vet.Estimated change as percentage from baseline with cell color representing low (red = 0%) to high (blue = 100%) reduction in pain outcomes.c Involves cell transplantation after discectomy has already been able to provide pain relief.d Cell transplantation was performed concurrently with microdiscectomy.

(
range: 25.0-76.6),a median ODI of 23.3 (range: 2.0-45.4),and 22.0 (range: 4.3-34.4)was achieved at the 6-and 12-month follow-ups, respectively (Table 3 and Data S6a).This equates to a median change of 24.0 (range: 1.0-62.3)and 27.2 (range: 10.0-52.0)ODI at the 6-and 12-month follow-ups, respectively.Again, the trends between PRP and cell-treated cohorts were similar, although PRP trials did not include any results after 12 months of follow-up (Data S6).Estimating the overall average ODI and ODI reduction values by weighing each study result by the cohort sample size (Figure 5e-h) showed an overall trend of ODI reduction from baseline score of 48.4 24.2 (N = 595), 22.0 (N = 514), and 19.1 (N = 135) at 6, 12, and 24 months, respectively (Figure 5e).Alternatively, 26.0 (N = 595), 27.0 (N = 523), and 29.2 (N = 135) ODI reductions at 6, 12, and 24 months, respectively, were calculated (Figure 5f).Here, PRP treatment appeared to result in slightly enhanced improvements compared to cell-treated cohorts, although it should be considered that the results were derived from a small selection of studies with small sample sizes, as well as missing long-term follow-up results (Figure 5g,h).Specifically, PRP products showed an overall reduction of 31.3 (N = 208) and 37.4 (N = 107) ODI at 6 and 12 months, respectively, compared to 22.4 (N = 402) and 24.3 (N = 416) for cell-based products.In contrast, MCID comparisons (excluding Meisel et al.) resulted in similar rates of success between cell-and PRP-based products.Cell therapeutics reported

F I G U R E 5
Trends in pain and ODI alleviation following cell and platelet-rich plasma (PRP) transplantation.(A) General trends of pain scores in identified trial weighted by sample size and similarly (b) the trend in pain score changes reported.(C, D) General trends in pain and pain alleviation for PRP and cell-therapies.(E) General trends of ODI scores in identified trial weighted by sample size and similarly (F) the trend in ODI score changes reported.(G, H) General trends in ODI and ODI change for PRP and cell-therapies.Dots represent average values recorded at indicated time point and dashed line indicates 95% confidence interval.T A B L E 3 Tabular overview of reported disability improvements.mental components.The physical component summary score increases ranged from 15% to 278%, with a median improvement of 75%.For the mental component summary, only a median improvement of 4% (range: À8% to 266%) was reported.

58 b
Table of all identifiedstudies and a summarizing statement regarding the reported ODI scores and ODI improvements at the final follow-up time point.Abbreviations: AC, articular cartilage-derived chondrocytes; AD-MSC, adipose-derived mesenchymal stromal cells; BMA, bone marrow aspirate; BMC, bone marrow concentrate; BM-MSC, bone marrow-derived mesenchymal stromal cells; FU, follow-up (in years); IVD-C, intervertebral disc-derived cells; LP-PRP, leucocyte poor platelet-rich plasma; LR-PRP, leucocyte-rich platelet-rich plasma; MCID, minimally clinical important difference; MPC, mesenchymal precursor cells; NPC, nucleus pulposus cells; ODI, Oswestry disability index; PL, platelet lysate; PRP, platelet-rich plasma; SVF, stromal vascular fraction; UC-MSC, umbilical cord-derived mesenchymal stromal cells.a Following recommendations of Maughan and Lewis.Estimated change as percentage from baseline with cell color representing low (red = 0%) to high (blue = 100%) reduction in ODI outcomes.c Involves cell transplantation after discectomy has already been able to provide pain relief.d Cell transplantation was performed concurrently with microdiscectomy.

F I G U R E 6
Assessment of clinical impact and comparison to spinal fusion surgery of average (A) pain scores, (B) change in pain scores from baseline, (C) average Oswestry Disability Index (ODI), (D) change in ODI from baseline presented for combined or separate cell-and platelet-rich plasma (PRP) injection products.Dots represent average values recorded at indicated time point.(*) 1-month follow-up for cell therapy and PRP products, 1.5 months for spinal fusion.( †) Based on work of Ostelo and de Vet. 56( ‡) Outcomes from meta-analysis of Koenders et al. 55 ( ¶) Based on the recommendations by Fairbank et al. 72 ( §) Based on the recommendations by Johnsen et al. 57 (#) Based on the recommendations by Maughan and Lewis.

4. 3 |
Clinical significanceAnother approach to determine clinical significance is by employing "standards" indicating a minimal important change to have clinical impact, that is, MCID.In the comprehensive review of Ostelo and de Vet 56 for

4. 6 |
Future considerationsOur review critically assessed the outcomes reported from clinical trials on cell and PRP injections for LBP and neck pain.It is important to note, however, that the studies included in our review represent only a fraction of the clinical trials registered and completed on cell therapeutics for LBP.A recent comprehensive review by Ambrosio et al.highlighted that only 26.9% of registered trials have resulted in a scientific publication.82Furthermore, our analysis of the available reports revealed a generally disappointing quality in the descriptions of outcomes, study design, and statistical analyses.For instance, although many studies proposed using imaging modalities as an outcome measure, only 14 out of 68 studies (20.6%) actually included imagingrelated outcomes in their reporting.Given these findings, we urge the scientific community, including authors, peer-reviewers, and editors, to adopt more stringent standards for the quality and transparency of reporting in human clinical trials.Additionally, we strongly recommend that the Orthopedic Research Society (ORS) Spine Section take a leading role in establishing expert consensus and designing guidelines on the expected aspects of trials and outcome measures in regenerative medicine for disc degeneration and LBP.This will aid in the formidable task of potentially translating regenerative medicine toward commercialization and into clinical practice.66,83